Targeting Wnt Signaling: Can We Safely Eradicate Cancer Stem Cells?

Takahashi-Yanaga, Fumi; Kahn, Michaël

doi:10.1158/1078-0432.ccr-09-2943

Cited by 446 publications

(379 citation statements)

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“…Phosphorylation of β-catenin by GSK-3β promotes β-catenin degradation via the ubiquitin-proteasome pathway (26). Binding of Wnt ligands to their receptors activates the Wnt/β-catenin pathway through phosphorylation and resulting inhibition of GSK-3β, resulting in stabilization and nuclear translocation of β-catenin to generate a transcriptional complex that includes phosphorylated CREB, CREB-binding protein, or its protein homolog p300 and ultimately to expression of downstream target genes (26,41). Activation of ERK1/2 is known to induce phosphorylation of both CREB and GSK-3β, thereby increasing the free β-catenin protein pool (42).…”

Section: Discussionmentioning

confidence: 99%

Purinergic signaling in human pluripotent stem cells is regulated by the housekeeping gene encoding hypoxanthine guanine phosphoribosyltransferase

Mastrangelo

Kim

Miyanohara

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Lesch-Nyhan disease (LND) is an X-linked genetic disorder caused by mutations of the hypoxanthine guanine phosphoribosyltransferase (HPRT) purine biosynthesis gene and characterized by aberrant purine metabolism, deficient basal ganglia dopamine levels, dystonia, and severe neurobehavioral manifestations, including compulsive self-injurious behavior. Although available evidence has identified important roles for purinergic signaling in brain development, the mechanisms linking HPRT deficiency, purinergic pathways, and neural dysfunction of LND are poorly understood. In these studies aimed at characterizing purinergic signaling in HPRT deficiency, we used a lentivirus vector stably expressing an shRNA targeted to the HPRT gene to produce HPRT-deficient human CVB induced pluripotent stem cells and human HUES11 embryonic stem cells. Both CVB and HUES11 cells show >99% HPRT knockdown and demonstrate markedly decreased expression of the purinergic P2Y1 receptor mRNA. In CVB cells, P2Y1 mRNA and protein down-regulation by HPRT knockdown is refractory to activation by the P2Y1 receptor agonist ATP and shows aberrant purinergic signaling, as reflected by marked deficiency of the transcription factor pCREB and constitutive activation of the MAP kinases phospho-ERK1/2. Moreover, HPRT-knockdown CVB cells also demonstrate marked reduction of phosphorylated β-catenin. These results indicate that the housekeeping gene HPRT regulates purinergic signaling in pluripotent human stem cells, and that this regulation occurs at least partly through aberrant P2Y1-mediated expression and signaling. We propose that such mechanisms may play a role in the neuropathology of HPRT-deficiency LND and may point to potential molecular targets for modulation of this intractable neurological phenotype.neurodevelopment | neurotransmitters C omplete genetic deficiency of the enzyme hypoxanthine guanine phosphoribosyltransferase (HPRT) causes LeschNyhan disease (LND), an intractable neurobehavioral disorder characterized by hyperuricemia, cognitive impairment, dystonia with spasticity choreoathetosis and compulsive self-mutilation (1). The enzyme HPRT plays a major role in salvage purine biosynthesis by catalyzing the conversion of hypoxanthine and guanine to the nucleotides inosine monophosphate (IMP) and guanosine monophosphate (1, 2). HPRT deficiency leads to the hallmark biochemical defect in LND: greatly increased de novo purine synthesis, with resulting elevated levels of oxypurines and tissue accumulation of uric acid, gout, and life-threatening nephrolithiasis (3, 4). Although treatment with the xanthine oxidase inhibitor allopurinol effectively prevents hyperuricemia and renal damage in LND and thereby markedly extends the lifespan of patients, neither allopurinol nor any other treatment produces lasting improvement in neurological manifestations (5, 6).PET scanning and postmortem studies of brains from patients with LND have demonstrated decreased levels of dopamine, dopamine biosynthetic enzymes, and dopamine uptake in the basal ganglia (...

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Section: Discussionmentioning

confidence: 99%

Purinergic signaling in human pluripotent stem cells is regulated by the housekeeping gene encoding hypoxanthine guanine phosphoribosyltransferase

Mastrangelo

Kim

Miyanohara

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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“…The Wnt signaling pathway serves a key role in normal embryonic development and the central nervous system; in addition, it regulates cell growth, migration and differentiation. Evidence suggests that the Wnt signaling pathway is frequently dysregulated in the majority of cancer types (19); therefore, blocking the Wnt signaling pathway is a promising strategy for cancer treatment. β-catenin is a key component of the Wnt signaling pathway; cytoplasmic β-catenin is normally maintained at a low level by proteasomal degradation.…”

Section: Discussionmentioning

confidence: 99%

“…β-catenin is a key component of the Wnt signaling pathway; cytoplasmic β-catenin is normally maintained at a low level by proteasomal degradation. The binding of Wnt proteins to Frizzled receptors results in the accumulation of unphosphorylated β-catenin, which translocates into the nucleus and activates the expression of Wnt target genes, including c-Myc and cyclin D1 (19)(20)(21). c-Myc is the most commonly overexpressed oncogene in human cancer and is mutated in ~20% of human cancers (22).…”

Section: Discussionmentioning

confidence: 99%

Suppression of the Wnt signaling pathway may contribute to the inhibition of proliferation of human hepatocellular carcinoma SMMC-7721 cells by esculetin

Fan

Sun

et al. 2017

Oncology Letters

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Abstract. The aims of the present study were to investigate the effects of esculetin on the proliferation of human hepatocellular carcinoma SMMC-7721 cells and to determine the underlying mechanism behind this activity. An MTT assay was used to assess cell proliferation, reverse transcription-quantitative polymerase chain reaction was used to determine the relative mRNA expression levels of β-catenin, c-Myc and cyclin D1, and western blot analysis was utilized to determine the levels of the associated proteins. Compared with the dimethyl sulfoxide control, esculetin reduced the cell viability of SMMC-7721 and HL-7702 cells in a dose-and time-dependent manner. Treatment of SMMC-7721 cells with esculetin resulted in downregulation of the mRNA and protein levels of β-catenin, c-Myc and cyclin D1. Esculetin increased the phosphorylation of β-catenin at Ser33/Ser37/Thr41 and inhibited the proliferation of human hepatoma SMMC-7721 cells by suppressing the Wnt signaling pathway. The results of the present study suggest that esculetin inhibited the Wnt/β-catenin signaling pathway in SMMC-7721 cells and may have potential as an effective anti-cancer drug, acting to inhibit the Wnt/β-catenin signaling pathway.

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“…The activation of Wnt signaling contributes to the etiology of several human cancers and may participate in malignant metastasis Gao et al, 2014). While the Wnt/b-catenin pathway (known as canonical) plays a major role in Wnt signaling, there are also alternative (noncanonical) pathways, including the Wnt-planar cell polarity (PCP) and Wnt-Ca + 2 pathways (Takahashi-Yanaga and Kahn, 2010). The Wnt system regulates motility and invasion not only by the canonical pathway but also by the PCP pathway in neoplasia as well as in physiologic processes.…”

Section: Introductionmentioning

confidence: 99%

Downregulation of VANGL1 Inhibits Cellular Invasion Rather than Cell Motility in Hepatocellular Carcinoma Cells Without Stimulation

Ozan

ToyluAsli

Atabey

et al. 2015

Genetic Testing and Molecular Biomarkers

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Aims: The Wnt planar cell polarity (PCP) pathway is one of the Wnt pathways which plays a critical role in cell proliferation and fate. The VANGL1 protein is one of Wnt-PCP pathway components. It is known that Wnt-PCP pathway has major roles in cell motility but its role in hepatocellular carcinoma (HCC) progression through invasion and metastasis needs to be clarified. Methods: We silenced VANGL1 gene expression in the HepG2 HCC cell line by stable transfection with a vector containing siRNA template for VANGL1 and investigated the change in cell invasion and motility. Results: Transfected cells with the siRNA template showed significantly suppressed invasive capacity when compared to controls although cellular motility was only slightly affected. Conclusion: Our study showed a basal role for VANGL1 with respect to the invasive capacity of HCC cells. This suggests that the Wnt-PCP pathway may play a role in progression of HCC through cellular invasion but further studies are needed to clarify its role in cell motility.

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Targeting Wnt Signaling: Can We Safely Eradicate Cancer Stem Cells?

Cited by 446 publications

References 108 publications

Purinergic signaling in human pluripotent stem cells is regulated by the housekeeping gene encoding hypoxanthine guanine phosphoribosyltransferase

Purinergic signaling in human pluripotent stem cells is regulated by the housekeeping gene encoding hypoxanthine guanine phosphoribosyltransferase

Suppression of the Wnt signaling pathway may contribute to the inhibition of proliferation of human hepatocellular carcinoma SMMC-7721 cells by esculetin

Downregulation of VANGL1 Inhibits Cellular Invasion Rather than Cell Motility in Hepatocellular Carcinoma Cells Without Stimulation

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